Microtubular-targeted chemotherapy agents such as taxanes are among the most widely prescribed first- and second-line chemotherapy choices for patients with the most common malignancies including lung-, breast-, and prostate cancer. Unfortunately, primary resistance to taxanes is a common clinical problem. Thus, there is a need to find improved chemotherapy treatments.
Checkpoint with forkhead and ringfinger domains (CHFR) function to delay cell cycle entry into metaphase in response to mitotic stress. Cells that are deficient in this gene undergo apoptosis. CHFR has an N-terminal forkhead domain, a RING domain which functions as an E3-ubiqutin ligase, and a cysteine-rich C terminal domain, which mediates interactions with other proteins. Yu et al. report CHFR is required for tumor suppression and Aurora A regulation. See Nature genetics, 2005, 37:401-406. C-terminal region of CHFR has a poly-ADP ribose binding zinc-finger (PBZ) motif which mediates a protein-protein interaction with PARP1. See Kashima et al., J Biol Chem, 2012, 287:12975-12984.
Satoh et al. report epigenetic inactivation of (CHFR) and sensitivity to microtubule inhibitors in gastric cancer. Cancer research, 2003, 63:8606-8613. Methylation of CHFR is reported to be associated with sensitivity to chemotherapy agents. See Pelosof et al., Int J Cancer, 2014, 134:596-605; Brandes et al., Carcinogenesis, 2005, 26:1152-1156; and Wang et al., Int J Gynecol Cancer, 2011, 21:996-1003. Pillai et al. report CHFR protein expression predicts outcomes to taxane-based first line therapy in metastatic NSCLC. See Clinical cancer research: an official journal of the American Association for Cancer Research, 2013, 19:1603-1611.
Kouskoumvekaki et al. report selective PPARγ ligands with partial agonist binding properties by integrated in silico/in vitro work flow. J Chem Inf Model, 2013, 53(4):923-37. See also KR 2009053504, JP 11258732, US 2004/0180889, US 2005/0049267, and US 2009/0163545.
References cited herein are not an admission of prior art.